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D’Amico F, Lugarà C, Luppino G, Giuffrida C, Giorgianni Y, Patanè EM, Manti S, Gambadauro A, La Rocca M, Abbate T. The Influence of Neurotrophins on the Brain-Lung Axis: Conception, Pregnancy, and Neonatal Period. Curr Issues Mol Biol 2024; 46:2528-2543. [PMID: 38534776 PMCID: PMC10968818 DOI: 10.3390/cimb46030160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 03/28/2024] Open
Abstract
Neurotrophins (NTs) are four small proteins produced by both neuronal and non-neuronal cells; they include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). NTs can exert their action through both genomic and non-genomic mechanisms by interacting with specific receptors. Initial studies on NTs have identified them only as functional molecules of the nervous system. However, recent research have shown that some tissues and organs (such as the lungs, skin, and skeletal and smooth muscle) as well as some structural cells can secrete and respond to NTs. In addition, NTs perform several roles in normal and pathological conditions at different anatomical sites, in both fetal and postnatal life. During pregnancy, NTs are produced by the mother, placenta, and fetus. They play a pivotal role in the pre-implantation process and in placental and embryonic development; they are also involved in the development of the brain and respiratory system. In the postnatal period, it appears that NTs are associated with some diseases, such as sudden infant death syndrome (SIDS), asthma, congenital central hypoventilation syndrome (CCHS), and bronchopulmonary dysplasia (BPD).
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Affiliation(s)
| | | | | | | | | | | | - Sara Manti
- Pediatric Unit, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi”, AOUP G. Martino, University of Messina, Via Consolare Valeria 1, 98124 Messina, Italy; (F.D.); (C.L.); (G.L.); (C.G.); (Y.G.); (E.M.P.); (A.G.); (M.L.R.); (T.A.)
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Xu F, Zhao L, Zhuang J, Gao X. Peripheral Neuroplasticity of Respiratory Chemoreflexes, Induced by Prenatal Nicotinic Exposure: Implication for SIDS. Respir Physiol Neurobiol 2023; 313:104053. [PMID: 37019251 DOI: 10.1016/j.resp.2023.104053] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/23/2023] [Accepted: 04/02/2023] [Indexed: 04/05/2023]
Abstract
Sudden Infant Death Syndrome (SIDS) occurs during sleep in seemingly healthy infants. Maternal cigarette smoking and hypoxemia during sleep are assumed to be the major causal factors. Depressed hypoxic ventilatory response (dHVR) is observed in infants with high risk of SIDS, and apneas (lethal ventilatory arrest) appear during the fatal episode of SIDS. Disturbance of the respiratory center has been proposed to be involved, but the pathogenesis of SIDS is still not fully understood. Peripherally, the carotid body is critical to generate HVR, and bronchopulmonary and superior laryngeal C-fibers (PCFs and SLCFs) are important for triggering central apneas; however, their roles in the pathogenesis of SIDS have not been explored until recently. There are three lines of recently accumulated evidence to show the disorders of peripheral sensory afferent-mediated respiratory chemoreflexes in rat pups with prenatal nicotinic exposure (a SIDS model) in which acute severe hypoxia leads to dHVR followed by lethal apneas. (1) The carotid body-mediated HVR is suppressed with a reduction of the number and sensitivity of glomus cells. (2) PCF-mediated apneic response is largely prolonged via increased PCF density, pulmonary IL-1β and serotonin (5-hydroxytryptamine, 5-HT) release, along with the enhanced expression of TRPV1, NK1R, IL1RI and 5-HT3R in pulmonary C-neurons to strengthen these neural responses to capsaicin, a selective stimulant to C-fibers. (3) SLCF-mediated apnea and capsaicin-induced currents in superior laryngeal C-neurons are augmented by upregulation of TRPV1 expression in these neurons. These results, along with hypoxic sensitization/stimulation of PCFs, gain insight into the mechanisms of prenatal nicotinic exposure-induced peripheral neuroplasticity responsible for dHVR and long-lasting apnea during hypoxia in rat pups. Therefore, in addition to the disturbance in the respiratory center, the disorders of peripheral sensory afferent-mediated chemoreflexes may also be involved in respiratory failure and death denoted in SIDS victims.
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Wong-Riley MTT. The critical period: neurochemical and synaptic mechanisms shared by the visual cortex and the brain stem respiratory system. Proc Biol Sci 2021; 288:20211025. [PMID: 34493083 DOI: 10.1098/rspb.2021.1025] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
The landmark studies of Wiesel and Hubel in the 1960's initiated a surge of investigations into the critical period of visual cortical development, when abnormal visual experience can alter cortical structures and functions. Most studies focused on the visual cortex, with relatively little attention to subcortical structures. The goal of the present review is to elucidate neurochemical and synaptic mechanisms common to the critical periods of the visual cortex and the brain stem respiratory system in the normal rat. In both regions, the critical period is a time of (i) heightened inhibition; (ii) reduced expression of brain-derived neurotrophic factor (BDNF); and (iii) synaptic imbalance, with heightened inhibition and suppressed excitation. The last two mechanisms are contrary to the conventional premise. Synaptic imbalance renders developing neurons more vulnerable to external stressors. However, the critical period is necessary to enable each system to strengthen its circuitry, adapt to its environment, and transition from immaturity to maturity, when a state of relative synaptic balance is attained. Failure to achieve such a balance leads to neurological disorders.
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Affiliation(s)
- Margaret T T Wong-Riley
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Zhang Y, Sun Q, Fan A, Dong G. Isoflurane triggers the acute cognitive impairment of aged rats by damaging hippocampal neurons via the NR2B/CaMKII/CREB pathway. Behav Brain Res 2021; 405:113202. [PMID: 33636236 DOI: 10.1016/j.bbr.2021.113202] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/02/2021] [Accepted: 02/18/2021] [Indexed: 11/18/2022]
Abstract
Isoflurane was responsible for acute neuronal impairment, but its potential molecular mechanisms in damaging hippocampal neurons had not been clearly understood. This study aimed to explore the underlying mechanism of how isoflurane affected the cognitive function of aged rats by damaging the hippocampal neurons. Acute cognitive impairment was found in aged Wistar rats via Morris water maze test and Y-maze test after isoflurane anesthesia in a dose-dependent manner compared with the control group in vivo. Isoflurane also decreased the viabilities and strengthened the apoptotic potential of hippocampal neurons by damaging the mitochondria in a time-dependent manner compared with the control group which was reported by MTT, immunofluorescent assay, flow cytometry and western blot assay in vitro. Isoflurane jeopardized hippocampal neurons by directly inactivating the NR2B/CaMKII/CREB pathway and its harmful effects could be ameliorated by adding CaMKII activator CdCl2. These findings provided evidence that the cognitive ability of aged rats was injured by isoflurane exposure and isoflurane also inhibited the viability and enhanced the apoptosis of hippocampal neurons by damaging the mitochondria through inhibition of the NR2B/CaMKII/CREB pathway and its harmful roles could be partially ameliorated by CdCl2. Our study demonstrated that isoflurane could cause acute neuronal damage and we provided fresh insights that contributed to the safe use of anesthetic agents and the prevention of PND in elderly people.
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Affiliation(s)
- Yuangui Zhang
- Department of Anesthesiology, Weifang People's Hospital, No. 151, Guangwen Street, Kuiwen District, Weifang City, Shandong Province, 261000, China
| | - Qingqing Sun
- Department of Anesthesiology, Weifang People's Hospital, No. 151, Guangwen Street, Kuiwen District, Weifang City, Shandong Province, 261000, China
| | - Aixia Fan
- Department of Anesthesiology, Xintai People's Hospital, No. 1329, Xinfu Road, Xintai City, Shandong Province, 271200, China
| | - Guimin Dong
- Department of Anesthesiology, Weifang People's Hospital, No. 151, Guangwen Street, Kuiwen District, Weifang City, Shandong Province, 261000, China.
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Mechanisms underlying a critical period of respiratory development in the rat. Respir Physiol Neurobiol 2019; 264:40-50. [PMID: 30999061 DOI: 10.1016/j.resp.2019.04.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 04/05/2019] [Accepted: 04/10/2019] [Indexed: 01/13/2023]
Abstract
Twenty-five years ago, Filiano and Kinney (1994) proposed that a critical period of postnatal development constitutes one of the three risk factors for sudden infant death syndrome (SIDS). The underlying mechanism was poorly understood. In the last 17 years, much has been uncovered on this period in the rat. Against several expected trends of development, abrupt neurochemical, metabolic, ventilatory, and electrophysiological changes occur in the respiratory system at P12-13. This results in a transient synaptic imbalance with suppressed excitation and enhanced inhibition, and the response to acute hypoxia is the weakest at this time, both at the cellular and system's levels. The basis for the synaptic imbalance is likely to be contributed by a reduced expression of brain-derived neurotrophic factor (BDNF) and its TrkB receptors in multiple brain stem respiratory-related nuclei during the critical period. Exogenous BDNF or a TrkB agonist partially reverses the synaptic imbalance, whereas a TrkB antagonist accentuates the imbalance. A transient down-regulation of pituitary adenylate cyclase-activating polypeptide (PACAP) at P12 in respiratory-related nuclei also contributes to the vulnerability of this period. Carotid body denervation during this time or perinatal hyperoxia merely delays and sometimes prolongs, but not eliminate the critical period. The rationale for the necessity of the critical period in postnatal development is discussed.
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Mu L, Xia DD, Michalkiewicz T, Hodges M, Mouradian G, Konduri GG, Wong-Riley MTT. Effects of neonatal hyperoxia on the critical period of postnatal development of neurochemical expressions in brain stem respiratory-related nuclei in the rat. Physiol Rep 2019. [PMID: 29516654 PMCID: PMC5842315 DOI: 10.14814/phy2.13627] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
We have identified a critical period of respiratory development in rats at postnatal days P12‐13, when inhibitory influence dominates and when the response to hypoxia is at its weakest. This critical period has significant implications for Sudden Infant Death Syndrome (SIDS), the cause of which remains elusive. One of the known risk factors for SIDS is prematurity. A common intervention used in premature infants is hyperoxic therapy, which, if prolonged, can alter the ventilatory response to hypoxia and induce sustained inhibition of lung alveolar growth and pulmonary remodeling. The goal of this study was to test our hypothesis that neonatal hyperoxia from postnatal day (P) 0 to P10 in rat pups perturbs the critical period by altering the normal progression of neurochemical development in brain stem respiratory‐related nuclei. An in‐depth, semiquantitative immunohistochemical study was undertaken at P10 (immediately after hyperoxia and before the critical period), P12 (during the critical period), P14 (immediately after the critical period), and P17 (a week after the cessation of hyperoxia). In agreement with our previous findings, levels of cytochrome oxidase, brain‐derived neurotrophic factor (BDNF), TrkB (BDNF receptor), and several serotonergic proteins (5‐HT1A and 2A receptors, 5‐HT synthesizing enzyme tryptophan hydroxylase [TPH], and serotonin transporter [SERT]) all fell in several brain stem respiratory‐related nuclei during the critical period (P12) in control animals. However, in hyperoxic animals, these neurochemicals exhibited a significant fall at P14 instead. Thus, neonatal hyperoxia delayed but did not eliminate the critical period of postnatal development in multiple brain stem respiratory‐related nuclei, with little effect on the nonrespiratory cuneate nucleus.
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Affiliation(s)
- Lianwei Mu
- Departments of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Dong Dong Xia
- Departments of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Matthew Hodges
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Gary Mouradian
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Girija G Konduri
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Margaret T T Wong-Riley
- Departments of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
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Liu Q, Wong-Riley MTT. Pituitary adenylate cyclase-activating polypeptide: Postnatal development in multiple brain stem respiratory-related nuclei in the rat. Respir Physiol Neurobiol 2018; 259:149-155. [PMID: 30359769 DOI: 10.1016/j.resp.2018.10.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 09/26/2018] [Accepted: 10/20/2018] [Indexed: 11/17/2022]
Abstract
The pituitary adenylate cyclase-activating polypeptide (PACAP) plays an important role in anterior pituitary hormone secretion, neurotransmission, and the control of breathing. Mice lacking PACAP die suddenly mainly in the 2nd postnatal week, coinciding temporally with a critical period of respiratory development uncovered by our laboratory in the rat. The goal of the current study was to test our hypothesis that PACAP expression is reduced during the critical period in normal rats. We undertook immunohistochemistry and optical densitometry of PACAP (specifically PACAP38) in several brain stem respiratory-related nuclei of postnatal days P2-21 rats, and found that PACAP immunoreactivity was significantly reduced at P12 in the pre-Bötzinger complex, nucleus ambiguus, hypoglossal nucleus, and the ventrolateral subnucleus of the nucleus tractus solitarius. No changes were observed in the control, non-respiratory cuneate nucleus at P12. Results imply that the down-regulation of PACAP during normal postnatal development may contribute to the critical period of vulnerability, when the animals' response to hypoxia is at its weakest.
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Affiliation(s)
- Qiuli Liu
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Margaret T T Wong-Riley
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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Zhang H, Mu L, Wang D, Xia D, Salmon A, Liu Q, Wong‐Riley MTT. Uncovering a critical period of synaptic imbalance during postnatal development of the rat visual cortex: role of brain-derived neurotrophic factor. J Physiol 2018; 596:4511-4536. [PMID: 30055019 PMCID: PMC6138289 DOI: 10.1113/jp275814] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 07/26/2018] [Indexed: 01/17/2023] Open
Abstract
KEY POINTS With daily electrophysiological recordings and neurochemical analysis, we uncovered a transient period of synaptic imbalance between enhanced inhibition and suppressed excitation in rat visual cortical neurons from the end of the fourth toward the end of the fifth postnatal weeks. The expression of brain-derived neurotrophic factor (BDNF), which normally enhances excitation and suppresses inhibition, was down-regulated during that time, suggesting that this may contribute to the inhibition/excitation imbalance. An agonist of the BDNF receptor tropomyosin-related kinase B (TrkB) partially reversed the imbalance, whereas a TrkB antagonist accentuated the imbalance during the transient period. Monocular lid suture during the transient period is more detrimental to the function and neurochemical properties of visual cortical neurons than before or after this period. We regard the period of synaptic imbalance as the peak critical period of vulnerability, and its existence is necessary for neurons to transition from immaturity to a more mature state of functioning. ABSTRACT The mammalian visual cortex is immature at birth and undergoes postnatal structural and functional adjustments. The exact timing of the vulnerable period in rodents remains unclear. The critical period is characterized by inhibitory GABAergic maturation reportedly dependent on brain-derived neurotrophic factor (BDNF). However, most of the studies were performed on experimental/transgenic animals, questioning the relationship in normal animals. The present study aimed to conduct in-depth analyses of the synaptic and neurochemical development of visual cortical neurons in normal and monocularly-deprived rats and to determine specific changes, if any, during the critical period. We found that (i) against a gradual increase in excitation and inhibition with age, a transient period of synaptic and neurochemical imbalance existed with suppressed excitation and enhanced inhibition at postnatal days 28 to 33/34; (ii) during this window, the expression of BDNF and tropomyosin-related kinase B (TrkB) receptors decreased, along with glutamatergic GluN1 and GluA1 receptors and the metabolic marker cytochrome oxidase, whereas that of GABAA Rα1 receptors continued to rise; (iii) monocular deprivation reduced both excitatory and inhibitory synaptic activity and neurochemicals mainly during this period; and (iv) in vivo TrkB agonist partially reversed the synaptic imbalance in normal and monocularly-deprived neurons during this time, whereas a TrkB antagonist accentuated the imbalance. Thus, our findings highlight a transitory period of synaptic imbalance with a negative relationship between BDNF and inhibitory GABA. This brief critical period may be necessary in transitioning from an immature to a more mature state of visual cortical functioning.
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Affiliation(s)
- Hanmeng Zhang
- Department of Cell Biology, Neurobiology and AnatomyMedical College of WisconsinMilwaukeeWIUSA
| | - Lianwei Mu
- Department of Cell Biology, Neurobiology and AnatomyMedical College of WisconsinMilwaukeeWIUSA
| | - Dandan Wang
- Department of Cell Biology, Neurobiology and AnatomyMedical College of WisconsinMilwaukeeWIUSA
| | - Dongdong Xia
- Department of Cell Biology, Neurobiology and AnatomyMedical College of WisconsinMilwaukeeWIUSA
| | - Alexander Salmon
- Department of Cell Biology, Neurobiology and AnatomyMedical College of WisconsinMilwaukeeWIUSA
| | - Qiuli Liu
- Department of Cell Biology, Neurobiology and AnatomyMedical College of WisconsinMilwaukeeWIUSA
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Alcalde LA, de Freitas BS, Machado GDB, de Freitas Crivelaro PC, Dornelles VC, Gus H, Monteiro RT, Kist LW, Bogo MR, Schröder N. Iron chelator deferiprone rescues memory deficits, hippocampal BDNF levels and antioxidant defenses in an experimental model of memory impairment. Biometals 2018; 31:927-940. [PMID: 30117045 DOI: 10.1007/s10534-018-0135-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 08/12/2018] [Indexed: 12/18/2022]
Abstract
Brain-derived neurotrophic factor (BDNF) plays a key role in neural development and physiology, as well as in pathological states. Post-mortem studies demonstrate that BDNF is reduced in the brains of patients affected by neurodegenerative diseases. Iron accumulation has also been associated to the pathogenesis of neurodegenerative diseases. In rats, iron overload induces persistent memory deficits, increases oxidative stress and apoptotic markers, and decreases the expression of the synaptic marker, synaptophysin. Deferiprone (DFP) is an oral iron chelator used for the treatment of systemic iron overload disorders, and has recently been tested for Parkinson's disease. Here, we investigated the effects of iron overload on BDNF levels and on mRNA expression of genes encoding TrkB, p75NTR, catalase (CAT) and NQO1. We also aimed at investigating the effects of DFP on iron-induced impairments. Rats received iron or vehicle at postnatal days 12-14 and when adults, received chronic DFP or water (vehicle). Recognition memory was tested 19 days after the beginning of chelation therapy. BDNF measurements and expression analyses in the hippocampus were performed 24 h after the last day of DFP treatment. DFP restored memory and increased hippocampal BDNF levels, ameliorating iron-induced effects. Iron overload in the neonatal period reduced, while treatment with DFP was able to rescue, the expression of antioxidant enzymes CAT and NQO1.
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Affiliation(s)
- Luisa Azambuja Alcalde
- Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, 90619-900, Brazil
| | - Betânia Souza de Freitas
- Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, 90619-900, Brazil
| | - Gustavo Dalto Barroso Machado
- Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, 90619-900, Brazil
| | - Pedro Castilhos de Freitas Crivelaro
- Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, 90619-900, Brazil
| | - Victoria Campos Dornelles
- Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, 90619-900, Brazil
| | - Henrique Gus
- Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, 90619-900, Brazil
| | - Ricardo Tavares Monteiro
- Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, 90619-900, Brazil
| | - Luiza Wilges Kist
- Laboratory of Genomics and Molecular Biology, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, 90619-900, Brazil.,Graduate Program in Medicine and Health Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, 90610-000, Brazil
| | - Mauricio Reis Bogo
- Laboratory of Genomics and Molecular Biology, Faculty of Biosciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, 90619-900, Brazil.,Graduate Program in Medicine and Health Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, 90610-000, Brazil
| | - Nadja Schröder
- Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite, 500, Porto Alegre, RS, 90050-170, Brazil. .,National Institute of Science and Technology for Translational Medicine (INCT-TM), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brasília, 71605-001, Brazil.
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Selective Requirement for Maintenance of Synaptic Contacts onto Motoneurons by Target-Derived trkB Receptors. Neural Plast 2016; 2016:2371893. [PMID: 27433358 PMCID: PMC4940568 DOI: 10.1155/2016/2371893] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 06/07/2016] [Indexed: 11/17/2022] Open
Abstract
Synaptic contacts onto motoneurons were studied in mice in which the gene for the trkB neurotrophin receptor was knocked out selectively in a subset of spinal motoneurons. The extent of contacts by structures immunoreactive for either of two different vesicular glutamate transporters (VGLUT1 and VGLUT2), the vesicular GABA transporter, or glutamic acid decarboxylase 67 (GAD67) with the somata of motoneurons, was studied in wild type and trkB knockout cells in tamoxifen treated male and female SLICK-trkB−/− mice. Selective knockout of the trkB gene resulted in a marked reduction in contacts made by VGLUT2- and GAD67-immunoreactive structures in both sexes and a significant reduction in contacts containing only glycine in male mice. No reduction was found for glycinergic contacts in female mice or for VGLUT1 immunoreactive contacts in either sex. Signaling through postsynaptic trkB receptors is considered to be an essential part of a cellular mechanism for maintaining the contacts of some, but not all, synaptic contacts onto motoneurons.
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Carrascal L, Nieto-González J, Pardillo-Díaz R, Pásaro R, Barrionuevo G, Torres B, Cameron WE, Núñez-Abades P. Time windows for postnatal changes in morphology and membrane excitability of genioglossal and oculomotor motoneurons. World J Neurol 2015; 5:113-131. [DOI: 10.5316/wjn.v5.i4.113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 10/07/2015] [Accepted: 12/08/2015] [Indexed: 02/06/2023] Open
Abstract
Time windows for postnatal changes in morphology and membrane excitability of genioglossal (GG) and oculomotor (OCM) motoneurons (MNs) are yet to be fully described. Analysis of data on brain slices in vitro of the 2 populations of MNs point to a well-defined developmental program that progresses with common age-related changes characterized by: (1) increase of dendritic surface along with length and reshaping of dendritic tree complexity; (2) disappearance of gap junctions early in development; (3) decrease of membrane passive properties, such as input resistance and time constant, together with an increase in the number of cells displaying sag, and modifications in rheobase; (4) action potential shortening and afterhyperpolarization; and (5) an increase in gain and maximum firing frequency. These modifications take place at different time windows for each motoneuronal population. In GG MNs, active membrane properties change mainly during the first postnatal week, passive membrane properties in the second week, and dendritic increasing length and size in the third week of development. In OCM MNs, changes in passive membrane properties and growth of dendritic size take place during the first postnatal week, while active membrane properties and rheobase change during the second and third weeks of development. The sequential order of changes is inverted between active and passive membrane properties, and growth in size does not temporally coincide for both motoneuron populations. These findings are discussed on the basis of environmental cues related to maturation of the respiratory and OCM systems.
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Gao XP, Zhang H, Wong-Riley M. Role of brain-derived neurotrophic factor in the excitatory-inhibitory imbalance during the critical period of postnatal respiratory development in the rat. Physiol Rep 2015; 3:3/11/e12631. [PMID: 26603459 PMCID: PMC4673652 DOI: 10.14814/phy2.12631] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 10/26/2015] [Indexed: 01/08/2023] Open
Abstract
The critical period of respiratory development in rats is a narrow window toward the end of the second postnatal week (P12–13), when abrupt neurochemical, electrophysiological, and ventilatory changes occur, when inhibition dominates over excitation, and when the animals’ response to hypoxia is the weakest. The goal of this study was to further test our hypothesis that a major mechanism underlying the synaptic imbalance during the critical period is a reduced expression of brain-derived neurotrophic factor (BDNF) and its TrkB receptors. Our aims were to determine (1) that the inhibitory dominance observed in hypoglossal motoneurons during the critical period was also demonstrable in a key respiratory chemosensor, NTSVL; (2) if in vivo application of a TrkB agonist, 7,8-DHF, would prevent, but a TrkB antagonist, ANA-12, would accentuate the synaptic imbalance; and (3) if hypoxia would also heighten the imbalance. Our results indicate that (1) the synaptic imbalance was evident in the NTSVL during the critical period; (2) intraperitoneal injections of 7,8-DHF prevented the synaptic imbalance during the critical period, whereas ANA-12 in vivo accentuated such an imbalance; and (3) acute hypoxia induced the weakest response in both the amplitude and frequency of sEPSCs during the critical period, but it increased the frequency of sIPSCs during the critical period. Thus, our findings are consistent with and strengthen our hypothesis that BDNF and TrkB play a significant role in inducing a synaptic imbalance during the critical period of respiratory development in the rat.
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Affiliation(s)
- Xiu-Ping Gao
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Hanmeng Zhang
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Margaret Wong-Riley
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
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Abstract
Brain-derived neurotrophic factor (BDNF) supports innervation of the carotid body by neurons projecting from the petrosal ganglion. Although carotid body glomus cells also express TrkB, BDNF's high affinity receptor, the role of BDNF in carotid body growth and O2 sensitivity has not been studied. Neonatal rats were treated with the TrkB antagonist K252a (100 μg kg(-1), i.p., b.i.d.) or vehicle on postnatal days P0-P6 and studied on P7. Carotid body volume was decreased by 35% after chronic K252a (P<0.001); a reduction in carotid body size was also elicited using the more selective TrkB antagonist ANA-12 (500 μg kg(-1), i.p., b.i.d.). In contrast, single-unit chemoafferent responses to 5% O2, measured in vitro, were unaffected by chronic K252a administration. Normoxic and hypoxic ventilation, measured by head-body plethysmography, were also normal after chronic K252a administration, but acute K252a administration produced a slower, deeper breathing pattern during the transition into hypoxia. These data suggest that BDNF regulates postnatal carotid body growth but does not influence the development of glomus cell O2 sensitivity.
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